Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUZIXUZ)

• DOT Name: PH and SEC7 domain-containing protein 1 (PSD)
• Synonyms: Exchange factor for ADP-ribosylation factor guanine nucleotide factor 6; Exchange factor for ARF6; Exchange factor for ARF6 A; Pleckstrin homology and SEC7 domain-containing protein 1
• Gene Name: PSD
• Related Disease:
  Colorectal carcinoma
  Intellectual disability
  Alzheimer disease
  Androgen insensitivity syndrome
  Attention deficit hyperactivity disorder
  Autism
  Autism spectrum disorder
  Bipolar disorder
  Childhood apraxia of speech
  Gastric cancer
  Inborn error of metabolism
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Mental disorder
  Neoplasm
  Recessive X-linked ichthyosis
  Schizophrenia
  Stomach cancer
  Stroke
  Ulcerative colitis
  Colon cancer
  Colon carcinoma
  Protein S deficiency
  Venous thromboembolism
  Adult glioblastoma
  Glioblastoma multiforme
  Glioma
  Advanced cancer
  Atrial septal defect
  Neurodevelopmental disorder
  Pervasive developmental disorder
  Post-traumatic stress disorder
  Toxoplasmosis
• UniProt ID: PSD1_HUMAN
• Pfam ID: PF15410 ; PF01369
• Sequence:
  MAQGAMRFCSEGDCAISPPRCPRRWLPEGPVPQSPPASMYGSTGSLLRRVAGPGPRGREL
  GRVTAPCTPLRGPPSPRVAPSPWAPSSPTGQPPPGAQSSVVIFRFVEKASVRPLNGLPAP
  GGLSRSWDLGGVSPPRPTPALGPGSNRKLRLEASTSDPLPARGGSALPGSRNLVHGPPAP
  PQVGADGLYSSLPNGLGGPPERLATLFGGPADTGFLNQGDTWSSPREVSSHAQRIARAKW
  EFFYGSLDPPSSGAKPPEQAPPSPPGVGSRQGSGVAVGRAAKYSETDLDTVPLRCYRETD
  IDEVLAEREEADSAIESQPSSEGPPGTAYPPAPRPGPLPGPHPSLGSGNEDEDDDEAGGE
  EDVDDEVFEASEGARPGSRMPLKSPVPFLPGTSPSADGPDSFSCVFEAILESHRAKGTSY
  TSLASLEALASPGPTQSPFFTFELPPQPPAPRPDPPAPAPLAPLEPDSGTSSAADGPWTQ
  RGEEEEAEARAKLAPGREPPSPCHSEDSLGLGAAPLGSEPPLSQLVSDSDSELDSTERLA
  LGSTDTLSNGQKADLEAAQRLAKRLYRLDGFRKADVARHLGKNNDFSKLVAGEYLKFFVF
  TGMTLDQALRVFLKELALMGETQERERVLAHFSQRYFQCNPEALSSEDGAHTLTCALMLL
  NTDLHGHNIGKRMTCGDFIGNLEGLNDGGDFPRELLKALYSSIKNEKLQWAIDEEELRRS
  LSELADPNPKVIKRISGGSGSGSSPFLDLTPEPGAAVYKHGALVRKVHADPDCRKTPRGK
  RGWKSFHGILKGMILYLQKEEYKPGKALSETELKNAISIHHALATRASDYSKRPHVFYLR
  TADWRVFLFQAPSLEQMQSWITRINVVAAMFSAPPFPAAVSSQKKFSRPLLPSAATRLSQ
  EEQVRTHEAKLKAMASELREHRAAQLGKKGRGKEAEEQRQKEAYLEFEKSRYSTYAALLR
  VKLKAGSEELDAVEAALAQAGSTEDGLPPSHSSPSLQPKPSSQPRAQRHSSEPRPGAGSG
  RRKP
• Function: Guanine nucleotide exchange factor for ARF6. Induces cytoskeletal remodeling.
• Tissue Specificity: Isoform 2 is expressed in the brain.
• KEGG Pathway: Endocytosis (hsa04144)

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Genetic Variation	[1]
Intellectual disability	DISMBNXP	Definitive	Genetic Variation	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
Androgen insensitivity syndrome	DISUZBBO	Strong	Biomarker	[4]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[5]
Autism	DISV4V1Z	Strong	Biomarker	[6]
Autism spectrum disorder	DISXK8NV	Strong	Biomarker	[7]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[8]
Childhood apraxia of speech	DISIR974	Strong	Biomarker	[9]
Gastric cancer	DISXGOUK	Strong	Biomarker	[10]
Inborn error of metabolism	DISO5FAY	Strong	Biomarker	[11]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[12]
Lung cancer	DISCM4YA	Strong	Biomarker	[12]
Lung carcinoma	DISTR26C	Strong	Biomarker	[12]
Mental disorder	DIS3J5R8	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Recessive X-linked ichthyosis	DISZY56W	Strong	Biomarker	[11]
Schizophrenia	DISSRV2N	Strong	Biomarker	[15]
Stomach cancer	DISKIJSX	Strong	Biomarker	[10]
Stroke	DISX6UHX	Strong	Biomarker	[16]
Ulcerative colitis	DIS8K27O	Strong	Posttranslational Modification	[17]
Colon cancer	DISVC52G	moderate	Genetic Variation	[18]
Colon carcinoma	DISJYKUO	moderate	Genetic Variation	[18]
Protein S deficiency	DISORLOT	moderate	Biomarker	[19]
Venous thromboembolism	DISUR7CR	moderate	Biomarker	[19]
Adult glioblastoma	DISVP4LU	Disputed	Biomarker	[20]
Glioblastoma multiforme	DISK8246	Disputed	Biomarker	[20]
Glioma	DIS5RPEH	Disputed	Biomarker	[20]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[21]
Atrial septal defect	DISJT76B	Limited	Biomarker	[22]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[23]
Pervasive developmental disorder	DIS51975	Limited	Biomarker	[23]
Post-traumatic stress disorder	DISHL1EY	Limited	Biomarker	[24]
Toxoplasmosis	DISYP8FH	Limited	Biomarker	[25]

5 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of PH and SEC7 domain-containing protein 1 (PSD).	[26]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of PH and SEC7 domain-containing protein 1 (PSD).	[27]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of PH and SEC7 domain-containing protein 1 (PSD).	[28]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of PH and SEC7 domain-containing protein 1 (PSD).	[29]
Aspirin	DM672AH	Approved	Aspirin increases the expression of PH and SEC7 domain-containing protein 1 (PSD).	[30]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of PH and SEC7 domain-containing protein 1 (PSD).	[31]

References

• [1] Aberrant methylation of PSD disturbs Rac1-mediated immune responses governing neutrophil chemotaxis and apoptosis in ulcerative colitis-associated carcinogenesis.Int J Oncol. 2012 Apr;40(4):942-50. doi: 10.3892/ijo.2011.1301. Epub 2011 Dec 15.
• [2] Altered Behaviors and Impaired Synaptic Function in a Novel Rat Model With a Complete Shank3 Deletion.Front Cell Neurosci. 2019 Mar 26;13:111. doi: 10.3389/fncel.2019.00111. eCollection 2019.
• [3] Effect of intraperitoneal or intracerebroventricular injection of streptozotocin on learning and memory in mice.Exp Ther Med. 2018 Sep;16(3):2375-2380. doi: 10.3892/etm.2018.6487. Epub 2018 Jul 19.
• [4] EFA6 regulates selective polarised transport and axon regeneration from the axon initial segment.J Cell Sci. 2017 Nov 1;130(21):3663-3675. doi: 10.1242/jcs.207423. Epub 2017 Sep 21.
• [5] Exome chip analyses in adult attention deficit hyperactivity disorder.Transl Psychiatry. 2016 Oct 18;6(10):e923. doi: 10.1038/tp.2016.196.
• [6] Evidence for a susceptibility gene for autism on chromosome 2 and for genetic heterogeneity.Am J Hum Genet. 2001 Jun;68(6):1514-20. doi: 10.1086/320588. Epub 2001 May 14.
• [7] Analysis of a Sardinian Multiplex Family with Autism Spectrum Disorder Points to Post-Synaptic Density Gene Variants and Identifies CAPG as a Functionally Relevant Candidate Gene.J Clin Med. 2019 Feb 7;8(2):212. doi: 10.3390/jcm8020212.
• [8] Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder.Neuropsychopharmacology. 2008 Aug;33(9):2175-86. doi: 10.1038/sj.npp.1301604. Epub 2007 Nov 21.
• [9] Estimates of the prevalence of speech and motor speech disorders in adolescents with Down syndrome.Clin Linguist Phon. 2019;33(8):772-789. doi: 10.1080/02699206.2019.1595735.
• [10] Genome-wide analysis of histone modifications by ChIP-chip to identify silenced genes in gastric cancer.Oncol Rep. 2015 May;33(5):2567-74. doi: 10.3892/or.2015.3824. Epub 2015 Feb 27.
• [11] Placental sulfatase deficiency: maternal and fetal expression of steroid sulfatase deficiency and X-linked ichthyosis.Obstet Gynecol Surv. 1986 Jul;41(7):401-13.
• [12] Proscillaridin A Promotes Oxidative Stress and ER Stress, Inhibits STAT3 Activation, and Induces Apoptosis in A549 Lung Adenocarcinoma Cells.Oxid Med Cell Longev. 2018 Jan 11;2018:3853409. doi: 10.1155/2018/3853409. eCollection 2018.
• [13] Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders. Nat Commun. 2019 Oct 15;10(1):4679. doi: 10.1038/s41467-019-12435-8.
• [14] Multifunctional Nanoparticles Loading with Docetaxel and GDC0941 for Reversing Multidrug Resistance Mediated by PI3K/Akt Signal Pathway.Mol Pharm. 2017 Apr 3;14(4):1120-1132. doi: 10.1021/acs.molpharmaceut.6b01045. Epub 2017 Mar 22.
• [15] Translating preclinical findings in clinically relevant new antipsychotic targets: focus on the glutamatergic postsynaptic density. Implications for treatment resistant schizophrenia.Neurosci Biobehav Rev. 2019 Dec;107:795-827. doi: 10.1016/j.neubiorev.2019.08.019. Epub 2019 Aug 25.
• [16] High serum levels of 8-OHdG are an independent predictor of post-stroke depression in Chinese stroke survivors.Neuropsychiatr Dis Treat. 2018 Feb 19;14:587-596. doi: 10.2147/NDT.S155144. eCollection 2018.
• [17] Aberrant methylation of the Pleckstrin and Sec7 domain-containing gene is implicated in ulcerative colitis-associated carcinogenesis through its inhibitory effect on apoptosis.Int J Oncol. 2012 Mar;40(3):686-94. doi: 10.3892/ijo.2011.1231. Epub 2011 Oct 13.
• [18] Immune Effects of M51R Vesicular Stomatitis Virus Treatment of Carcinomatosis From Colon Cancer.J Surg Res. 2020 Jan;245:127-135. doi: 10.1016/j.jss.2019.07.032. Epub 2019 Aug 12.
• [19] Role of protein S deficiency in children with venous thromboembolism. An observational international cohort study.Thromb Haemost. 2015 Feb;113(2):426-33. doi: 10.1160/TH14-06-0533. Epub 2014 Oct 2.
• [20] EFA6A enhances glioma cell invasion through ADP ribosylation factor 6/extracellular signal-regulated kinase signaling.Cancer Res. 2006 Feb 1;66(3):1583-90. doi: 10.1158/0008-5472.CAN-05-2424.
• [21] The Pleckstrin and Sec7 domain-containing gene as a novel epigenetic modification marker in human gastric cancer and its clinical significance.Int J Oncol. 2015 Jan;46(1):195-204. doi: 10.3892/ijo.2014.2736. Epub 2014 Oct 30.
• [22] Maternal and offspring MTHFR gene C677T polymorphism as predictors of congenital atrial septal defect and patent ductus arteriosus.Mol Hum Reprod. 2006 Jan;12(1):51-4. doi: 10.1093/molehr/gah252. Epub 2005 Dec 22.
• [23] Postsynaptic density proteins and their involvement in neurodevelopmental disorders.J Biochem. 2018 Jun 1;163(6):447-455. doi: 10.1093/jb/mvy022.
• [24] Screening for posttraumatic stress disorder in young adult refugees from Syria and Iraq.Compr Psychiatry. 2019 Apr;90:73-81. doi: 10.1016/j.comppsych.2018.11.001. Epub 2018 Dec 14.
• [25] Monitoring of visual field over 6months after active ocular toxoplasmosis.Graefes Arch Clin Exp Ophthalmol. 2019 Jul;257(7):1481-1488. doi: 10.1007/s00417-019-04313-2. Epub 2019 Apr 29.
• [26] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [27] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [28] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [29] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [30] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [31] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.